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Respiratory Research Jun 2024Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance,...
BACKGROUND
Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH.
METHODS
Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction.
RESULTS
Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P < .0001) and had significant discriminative abilities (AUCs of 0.84, 0.82, and 0.91, respectively; P < .001). High resistin levels (above 4.54 ng/mL) in PAH patients were associated with older age (P = .001), shorter 6-min walk distance (P = .001), and reduced cardiac performance (cardiac index, P = .016). Interestingly, mutant carriers of either rs3219175 or rs3745367 had higher resistin levels (adjusted P = .0001). High resistin levels in PAH patients were also associated with increased risk of death (hazard ratio: 2.6; 95% CI: 1.27-5.33; P < .0087). Comparisons of ML-derived survival models confirmed satisfactory prognostic value of the random forest model (AUC = 0.70, 95% CI: 0.62-0.79) for PAH.
CONCLUSIONS
This work establishes the importance of resistin in the pathobiology of human PAH. In line with its function in rodent models, serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. ML-derived survival models highlighted the importance of including resistin levels to improve performance. Future studies are needed to develop multi-marker assays that improve noninvasive risk stratification.
Topics: Humans; Male; Female; Resistin; Middle Aged; Adult; Severity of Illness Index; Biomarkers; Predictive Value of Tests; Pulmonary Arterial Hypertension; Aged; Cohort Studies; Polymorphism, Single Nucleotide; Survival Rate; Hypertension, Pulmonary
PubMed: 38844967
DOI: 10.1186/s12931-024-02861-8 -
Neurobiology of Disease Aug 2024Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or...
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.
Topics: Animals; Neuroprotective Agents; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Mice, Inbred C57BL; Female; Humans; Intercellular Signaling Peptides and Proteins; Brain; Disease Models, Animal; Microglia; Apelin
PubMed: 38844244
DOI: 10.1016/j.nbd.2024.106552 -
Research in Veterinary Science Aug 2024The aim of the present study was to determine the effects of the adipokines progranulin and omentin on the basic functions of feline ovarian cells. For this purpose, we...
The aim of the present study was to determine the effects of the adipokines progranulin and omentin on the basic functions of feline ovarian cells. For this purpose, we investigated the effects of the addition of progranulin and omentin (0, 0.1, 1, or 10 ng/ml) on the proliferation (accumulation of PCNA and cyclin B1), apoptosis (accumulation of Bax and caspase 3) and progesterone release of cultured feline ovarian granulosa cells by quantitative immunocytochemistry and enzyme-linked immunosorbent assays (ELISAs). Both progranulin and omentin increased cell proliferation and decreased apoptosis. Both progranulin and omentin promoted progesterone release. The present findings demonstrate that the adipokines progranulin and omentin can directly regulate basic feline ovarian cell functions.
Topics: Animals; Female; Cats; Granulosa Cells; Apoptosis; Cell Proliferation; Progesterone; Progranulins; Cytokines; Cells, Cultured; Lectins
PubMed: 38843689
DOI: 10.1016/j.rvsc.2024.105321 -
Journal of Sports Science & Medicine Jun 2024Breast cancer survivors with obesity are at a high risk of cancer recurrence, comorbidity, and mortality. This review aims to systematically evaluate the effects of... (Meta-Analysis)
Meta-Analysis Review
Combined Aerobic and Resistance Training Improves Body Composition, Alters Cardiometabolic Risk, and Ameliorates Cancer-Related Indicators in Breast Cancer Patients and Survivors with Overweight/Obesity: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Breast cancer survivors with obesity are at a high risk of cancer recurrence, comorbidity, and mortality. This review aims to systematically evaluate the effects of combined aerobic and resistance training (CART) on body composition, lipid homeostasis, inflammation, adipokines, cancer-related fatigue, sleep, and quality of life in breast cancer patients and survivors with overweight/obesity. An electronic search was conducted in PubMed, Web of Science, Scopus, Science Direct, Cochrane, and Google Scholar databases from inception up to January 8, 2024. Randomized controlled trials (RCTs) meeting the inclusion criteria were selected for the analysis. The Cochrane risk of bias tool was used to assess eligible studies, and the GRADE method to evaluate the quality of evidence. A random-effects model was used, and data were analyzed using mean (MD) and standardized mean differences (SMD) for continuous variables with 95% confidence intervals (CI). We assessed the data for risk of bias, heterogeneity, sensitivity, reporting bias, and quality of evidence. A total of 17 randomized controlled trials were included in the systematic review involving 1,148 female patients and survivors (mean age: 54.0 ± 3.4 years). The primary outcomes showed significant improvements in body mass index (SMD -0.57 kg/m, = 0.04), body fat (SMD -0.50%, = 0.02), fat mass (SMD -0.63 kg, = 0.04), hip circumference (MD -3.14 cm, = 0.02), and fat-free mass (SMD 1.03 kg, < 0.001). The secondary outcomes indicated significant increases in high-density lipoprotein cholesterol (MD -0.05 mmol/L, = 0.008), natural killer cells (SMD 0.42%, = 0.04), reductions in triglycerides (MD -81.90 mg/dL, < 0.01), total cholesterol (SMD -0.95 mmol/L, < 0.01), tumor necrosis factor α (SMD -0.89 pg/mL, = 0.03), and leptin (SMD -0.63 ng/mL, = 0.03). Also, beneficial alterations were found in cancer-related fatigue (SMD -0.98, = 0.03), sleep (SMD -1.17, < 0.001), and quality of life (SMD 2.94, = 0.02) scores. There was very low to low confidence in the estimated effect of most of the outcomes. The present findings reveal that CART could be considered an adjunct therapy in supporting the conventional clinical approach observed following exercise. However, further high-quality research is needed to evaluate whether CART would be a valuable intervention to lower aggressive pharmacologic use in breast cancer patients with overweight/obesity.
Topics: Humans; Breast Neoplasms; Female; Resistance Training; Cancer Survivors; Randomized Controlled Trials as Topic; Body Composition; Obesity; Quality of Life; Cardiometabolic Risk Factors; Adipokines; Exercise; Fatigue; Sleep; Overweight
PubMed: 38841642
DOI: 10.52082/jssm.2024.366 -
Heliyon Jun 2024and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases....
OBJECTIVE
and design Mild vascular inflammation promotes the pathogenesis of hypertension. Asprosin, a newly discovered adipokine, is closely associated with metabolic diseases. We hypothesized that asprosin might led to vascular inflammation in hypertension via NLRP3 inflammasome formation. This study shows the importance of asprosin in the vascular inflammation of hypertension.
METHODS
Primary vascular smooth muscle cells (VSMCs) were obtained from the aorta of animals, including spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), NLRP3 and wild-type mice. Studies were performed in VSMCs , as well as WKY and SHR .
RESULTS
Asprosin expressions were up-regulated in VSMCs and media of arteries in SHR. Asprosin overexpression promoted NLRP3 inflammasome activation via Toll-like receptor 4 (TLR4), accompanied with activation of NFκB signaling pathway in VSMCs. Exogenous asprosin protein showed similar roles in promoting NLRP3 inflammasome activation. Knockdown of asprosin restrained NLRP3 inflammasome and p65-NFκB activation in VSMCs of SHR. NLRP3 inhibitor MCC950 or NFκB inhibitor BAY11-7082 attenuated asprosin-caused VSMC proliferation and migration. Asprosin-induced interleukin-1β production, proliferation and migration were attenuated in NLRP3 VSMCs. Local asprosin knockdown in common carotid artery of SHR attenuated inflammation and vascular remodeling.
CONCLUSIONS
Asprosin promoted NLRP3 inflammasome activation in VSMCs by TLR4-NFκB pathway, and thereby stimulates VSMCs proliferation, migration, and vascular remodeling of SHR.
PubMed: 38841464
DOI: 10.1016/j.heliyon.2024.e31659 -
Cellular and Molecular Biology... Jun 2024This study aimed to explore the regulatory effects and associated mechanisms of adiponectin on apoptosis and proliferation in the LN18 glioma cell line through the AMPK...
This study aimed to explore the regulatory effects and associated mechanisms of adiponectin on apoptosis and proliferation in the LN18 glioma cell line through the AMPK and Akt signaling pathways. Additionally, we sought to elucidate the impact of adiponectin on the chemosensitivity of the LN18 glioma cell line to temozolomide (TMZ). The proliferation rate of glioma cells treated with adiponectin was assessed using the cholecystokinin (CCK8) assay. The Western blot analysis was employed to assess the expression of p-Akt, p-AMPK, p-mTOR, cleaved caspase3, Bax, Cyclin D1, and Cyclin B1 following adiponectin treatment. Cell apoptosis was quantified using AnnexinV/PI flow cytometry, while changes in the cell cycle were detected using PI staining flow cytometry. The findings revealed that adiponectin upregulates p-AMPK expression and downregulates p-mTOR expression in the PTEN wild-type glioma cell line LN18, with no discernible effect on p-Akt expression. Moreover, adiponectin inhibits the proliferation rate of the PTEN wild-type glioma cell line LN18, enhances the expression of cleaved caspase3 and Bax, and significantly elevates the apoptosis rate, as evidenced by AnnexinV/PI flow cytometry. Adiponectin was observed to suppress the expression of Cyclin D1 and Cyclin B1, increase the number of cells in the G1 phase, and promote autophagy. Additionally, adiponectin augments the expression of Beclin1 and the ratio of LC3II/I in the PTEN wild-type glioma cell line LN18, while decreasing p62 expression. In conclusion, this study posits that adiponectin holds therapeutic promise for glioma treatment. Furthermore, adiponectin enhances the inhibitory effect of TMZ on the proliferation rate of LN18 cells when treated with 0.1 mM and 1 mM TMZ. These results collectively suggest that adiponectin impedes proliferation, encourages apoptosis and autophagy in the LN18 glioma cell line, and heightens its sensitivity to the chemotherapeutic drug TMZ.
Topics: Adiponectin; Apoptosis; Humans; Glioma; Autophagy; Cell Proliferation; Cell Line, Tumor; Temozolomide; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Signal Transduction; AMP-Activated Protein Kinases
PubMed: 38836664
DOI: 10.14715/cmb/2024.70.6.27 -
International Immunopharmacology Jul 2024Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts...
Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11 day till the 16 and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.
Topics: Animals; Asthma; Mice; Receptors, Adiponectin; Ovalbumin; Male; Signal Transduction; Disease Models, Animal; AMP-Activated Protein Kinases; Lung; Cytokines; Anti-Inflammatory Agents; Oxidative Stress; Adiponectin; Anti-Asthmatic Agents; Bronchoalveolar Lavage Fluid; Immunoglobulin E; Humans; Dexamethasone; Piperidines
PubMed: 38833845
DOI: 10.1016/j.intimp.2024.112395 -
International Journal of Surgery... Jun 2024Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and...
INTRODUCTION
Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and adipokines, including ghrelin and resistin, are linked to obesity, studies analyzing the changes in fasting ghrelin and resistin levels in patients following one anastomosis gastric bypass are lacking.
AIM
We aimed to investigate resistin and ghrelin levels before and after two commonly used bariatric procedures with different mechanisms of action: sleeve gastrectomy (SG) and one anastomosis gastric bypass (OAGB).
PATIENTS AND METHODS
Fasting serum ghrelin and resistin levels were evaluated by using ELISA in a non-randomized, prospective cohort study for the pattern of changes in the preoperative period and one week, one month, three months and, 12 months after surgery in age and sex-matched patients with BMI ≥40 kg/m2 undergoing either sleeve gastrectomy (n=40) or one anastomosis gastric bypass (n=40). Their relationships with demographic parameters such as body weight, Body mass index (BMI), presence of T2DM, HbA1C, and HOMA-IR index were also evaluated.
RESULTS
OAGB was superior in weight control compared to the SG group. There were significant differences in resistin and ghrelin levels between the OAGB and SG groups. Ghrelin decreased more in the SG group than the preoperative values. This change in ghrelin levels was more significant at one year after sleeve gastrectomy (preoperative mean(range) level of 334.2 (36.6-972.1) pg/mL decreased to 84 (9.1-227) pg/ml at one year) whereas in the OAGB group no significant change was observed (preoperative mean(range) level of 310 (146-548)pg/mL decreased to 264 (112-418)pg/mL at one year). Resistin levels decreased in both groups, especially after three months and onward following both operations (the mean(range) resistin levels were 2.6 (0.87-5.4)ng/mL and decreased to 1.1 (0.5-2.4)ng/mL in the SG group vs 2.48 (0.89-6.43)ng/mL decreased to 0.72 (0.35-1.8)ng/mL in OAGB group at one year), which was in parallel with changes in HOMA-IR index, body weight, and BMI changes at 1st year. HOMA-IR index changes were similar, but more prominent after OAGB. OAGB was also superior in T2DM control, parallel with weight loss, fasting resistin levels (especially after three months and onward), and HOMA-IR changes.
CONCLUSION
This is the first study to compare fasting ghrelin and resistin levels after one anastomosis gastric bypass and sleeve gastrectomy. Although similar changes were observed, ghrelin changes were more prominent after SG, whereas resistin were observed after OAGB. OAGB was superior in T2DM control which was in parallel with weight loss, fasting resistin levels, and HOMA-IR changes suggesting a possible effect of resistin after OAGB in glucose metabolism and insulin resistance.
PubMed: 38833355
DOI: 10.1097/JS9.0000000000001608 -
Journal of Molecular Endocrinology Aug 2024The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind...
Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high-fat diet-related insulin resistance, hepatic steatosis and adipose dysfunction.
The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind prolactin as well as the growth hormone receptor. To this end, a transgenic CD-1 mouse expressing human but not mouse growth hormone was generated, and the phenotypes of male mice fed with a regular chow or high-fat diet were assessed. Pancreas and epididymal white adipose tissue gene expression and/or related function were targeted as the pancreas responds to both prolactin and growth hormone receptor signaling, and catabolic effects like lipolytic activity are more directly attributable to growth hormone and growth hormone receptor signaling. The resulting human growth hormone-expressing mice are smaller than wild-type CD-1 mice, despite higher body fat and larger adipocytes, but both mouse types grow at the same rate with similar bone densities. Unlike wild-type mice, there was no significant delay in glucose clearance in human growth hormone-expressing mice when assessed at 8 versus 24 weeks on a high-fat diet. However, both mouse types showed signs of hepatic steatosis that correlated with elevated prolactin but not growth hormone RNA levels. The larger adipocytes in human growth hormone-expressing mice were associated with modified leptin (higher) and adiponectin (lower) RNA levels. Thus, while limited to observations in the male, the human growth hormone-expressing mice exhibit signs of growth hormone insufficiency and adipocyte dysfunction as well as an initial resistance to the negative effects of high-fat diet on glucose clearance.
Topics: Animals; Mice, Transgenic; Humans; Diet, High-Fat; Insulin Resistance; Fatty Liver; Mice; Male; Homeostasis; Glucose; Adipose Tissue; Human Growth Hormone; Growth Hormone; Prolactin; Leptin; Adipocytes; Adipose Tissue, White
PubMed: 38832641
DOI: 10.1530/JME-24-0026 -
Frontiers in Veterinary Science 2024Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and... (Review)
Review
Osteoartritis (OA) is a debilitating disease affecting both humans and animals. In the early stages, OA is characterized by damage to the extracellular matrix (ECM) and apoptosis and depletion of chondrocytes. OA progression is characterized by hyaline cartilage loss, chondrophyte and osteophyte formation, thickening of the joint capsule and function loss in the later stages. As the regenerative potential of cartilage is very limited and osteoarthritic changes are irreversible, prevention of OA, modulation of existing osteoarthritic joint inflammation, reducing joint pain and supporting joint function are the only options. Progression of OA and pain may necessitate surgical intervention with joint replacement or arthrodesis as end-stage procedures. In human medicine, the role of adipokines in the development and progression of OA has received increasing interest. At present, the known adipokines include leptin, adiponectin, visfatin, resistin, progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin. Adipokines have been demonstrated to play a pivotal role in joint homeostasis by modulating anabolic and catabolic balance, autophagy, apoptosis and inflammatory responses. In small animals, in terms of dogs and cats, naturally occurring OA has been clearly demonstrated as a clinical problem. Similar to humans, the etiology of OA is multifactorial and has not been fully elucidated. Humans, dogs and cats share many joint related degenerative diseases leading to OA. In this review, joint homeostasis, OA, adipokines and the most common joint diseases in small animals leading to naturally occurring OA and their relation with adipokines are discussed. The purpose of this review is highlighting the translational potential of OA and adipokines research in small animal patients.
PubMed: 38831954
DOI: 10.3389/fvets.2024.1193702